The present invention relates to methods of providing desired therapeutic effects to humans or animals using compositions including cyclosporine components. More particularly, the invention relates to methods of treating blepharospasm, for example, primary blepharospasm and/or benign essential blepharospasm, comprising administering to a human or animal afflicted with or having such blepharospasm a therapeutically effective amount of a cyclosporine component.
The use of cyclosporine A and cyclosporin A derivatives to treat ophthalmic conditions has been the subject of various patents, for example Ding et al U.S. Pat. No. 5,474,979; Garst U.S. Pat. No. 6,254,860; and Garst U.S. Pat. No. 6,350,442, this disclosure of each of which is incorporated in its entirely herein by reference.
In addition, a number of prior art patents have disclosed the use of cyclosporine, administered topically and/or systemically, as a treatment for other conditions and/or diseases.
Blepharospasm is a term used to describe a disease characterized by involuntary, inappropriate and/or excessive, forceful eye closure. It typically affects both eyes symmetrically, although sometimes there is marked asymmetry. Blepharospasm is an adult-onset focal dystonia characterized by involuntary muscle contractions, for example, contractions of the orbicularis oculic muscles. Benign essential blepharospasm (BEB) often is used to refer to a disease characterized by primary, bilateral blepharospasm without the involvement of the lower facial musculature. When blepharospasm is associated with oromandibular dystonia, laryngeal or cervical dystonia, the complex is called segmental cranial dystonia, or Meige's syndrome.
Primary blepharospasm, for example, BEB, like other presentations of focal, adult-onset idiopathic dystonia, typically begins insidiously in the 5th to 7th decade of life. Estimates of the prevalence of blepharospasm range from 16 to 133 per million people, and it is more common in women. Disease progression is generally very slow and although it usually remains focal, over decades the dystonic features may spread to nearby facial muscles or, less commonly, to other parts of the body. There may be a family history of blepharospasm, other focal dystonias, movement disorder or tics. Indeed, the fundamental cause or etiology of primary blepharospasm is typically unknown and it is therefore referred to as “idiopathic”, or idiopathic blepharospasm.
There may be a long prodrome of sensory symptoms such as photophobia and ocular discomfort. Initially, the dystonic muscle contractions are intermittent. If the disease progresses, the blepharospasm can increase in both frequency and intensity, leading to functional blindness in some patients. However, in the absence of therapy, some patients can have a protracted progression of symptoms. Primary blepharospasm may be task specific and occur mainly with certain activities, and not with others. It may be worse in bright light, and when the patient is tired, anxious or particularly needs to see. Many patients complain of worsening symptoms as the day wears on.
As with other focal dystonias, primary or idiopathic blepharospasm can be a prominent component of generalized primary (idiopathic torsion dystonia) and symptomatic dystonias.
For movement disorders in general, and for blepharospasm in this particular situation, we classify the disorder as a “primary” or “idiopathic” condition or a “secondary” or “symptomatic” condition. Idiopathic means without a known etiology or the presence of any other disorder that can present with the symptoms. Patients with idiopathic disease have no evidence by history, examination, or laboratory studies of any identifiable cause for the dystonic symptoms. Therefore, such patients have a normal perinatal and early developmental history, no prior history of neurologic illness or exposure to drugs known to cause acquired dystonia (e.g., phenothiazines), normal intellectual, pyramidal, cerebellar, and sensory examinations, and normal diagnostic studies. Patients who have abnormalities, such as those noted above, are classified as having secondary or symptomatic dystonia. In the case of blepharospasm, some patients present with evidence of one or more ocular surface conditions. However, the diagnosis of primary blepharospasm can be made with confidence when the increased eyeblinking persists after the ocular surface condition or conditions are treated.
Blepharospasm is seen in about a quarter of patients with progressive supranuclear palsy. This is an example of symptomatic blepharospasm. In patients with Parkinson's disease, an exaggerated blink reflex is through to be the basis of the Meyerson's sign, also known at the glabellar tap sign. Infrequently, patients with Parkinson's disease have significant blepharospasm superimposed on their hypomimia. Dystonic facial grimacing is also seen as a dystonic hyperkinesia associated with levodopa therapy. Secondary blepharospasm sometimes occurs in tardive dystonia.
The diagnosis of primary blepharospasm, such as BEB, is made on a typical history, even prior to the examination for physical signs. Patients may present to ophthalmologists with sore eyes. Even if slit lamp examination of the eyelids reveals chronic ocular surface disorders such as blepharitis, meibomian gland dysfunction or dry eyes, appropriate local treatment usually has no effect on the primary symptoms. It is possible that these disorders trigger primary blepharospasm in individuals who are genetically or otherwise susceptible.
Secondary blepharospasm may result from local ocular surface or oculosurface disease, for example, corneal irritation, corneal abrasions, keratoconjunctivitis sicca (dry eye) and the like. However, the characteristic fluctuations experienced by patients in primary or idiopathic blepharospasm are not evident in patients with this type of local oculosurface disease associated blepharospasm.
Thus, primary blepharospasm, for example, BEB, is different and distinct from blepharospasm associated with local oculosurface disease.
A study has been reported, in Sansom, J. et al, Treatment of Keratoconjunctivitis Sicca in Dogs with Cyclosporine Ophthalmic Ointment: a European Clinical Field Trial, The Veterinary Record, Nov. 11, 1995, in which dogs suffering from secondary blepharospasm caused by keratoconjunctivitis sicca were treated with cyclosporine ophthalmic ointment. The incidence of secondary blepharospasm, as well as other signs of discomfort and corneal oedema, was reported in this study as having decreased significantly over the course of the study.
A number of treatments have been suggested for primary blepharospasm. For example, injections of botulinum toxin have been found to be effective. Also, various drugs have been reported to be effective. Such drugs include:                Benzodiazepines (diazepam, clonazepam, lorazepam, oxazepam)        Anticholinergics (orphenadrine, trihexyphenidyl)        Serotonin antagonists (cyproheptadine)        Antipsychotics (phenothiazine, butyrophenone, reserpine)        Affective disorder agents (lithium carbonate, tetrabenazine)        Antianxiety agents (meprobamate)        Stimulants (amphetamine)        Sedatives (phenobarbital)        Parasympathomimetics (lecithin, choline, physostigmine)        Antimuscarinics (tincture of belladonna, scopolamine)        Antihistamines (diphenhydramine hydrochloride)        Gamma aminobutyric acid (GABA) agonists (baclofen)        
There continues to be a need for new methods of treating blepharospasm, for example, blepharospasm not caused by oculosurface disease, for example, not caused by keratoconjunctivitis sicca, such as primary blepharospasm, secondary blepharospasm in Parkinson's disease and secondary blepharospasm in tardive dystonia.